Buben J A, O'Flaherty E J
Toxicol Appl Pharmacol. 1985 Mar 30;78(1):105-22. doi: 10.1016/0041-008x(85)90310-2.
The relationship among dose, metabolism and hepatotoxicity in mice which resulted from subchronic exposure to the chlorinated solvents trichloroethylene (TRI) and perchloroethylene (PER) were examined. Male Swiss-Cox mice received either TRI (0 to 3200 mg/kg/day) of PER (0 to 2000 mg/kg/day) in corn oil by gavage for 6 weeks. Urinary metabolites from individual mice were quantified to estimate the extent to which each compound was metabolized. Four parameters of hepatotoxicity were assessed: liver weight, triglycerides, glucose-6-phosphatase (G6P) activity, and SGPT activity. TRI significantly affected liver weight and G6P activity; PER affected all four parameters. The metabolism of TRI was linearly related to dose through 1600 mg/kg, but then became saturated. The metabolism of PER was saturable. The dose-effect curves of the affected hepatotoxicity parameters of both compounds were nonlinear and resembled the dose-metabolism graph of the corresponding solvent. Plots of the hepatotoxicity data of each compound against total urinary metabolites were linear in all cases, suggesting that the hepatotoxicity of both PER and TRI in mice is directly related to the extent of their metabolism. This pattern is consistent with formation of the toxic intermediate in the primary metabolic pathway of each compound.
研究了小鼠亚慢性暴露于氯化溶剂三氯乙烯（TRI）和全氯乙烯（PER）后，剂量、代谢与肝毒性之间的关系。雄性瑞士-考克斯小鼠通过灌胃给予玉米油中的TRI（0至3200毫克/千克/天）或PER（0至2000毫克/千克/天），持续6周。对每只小鼠的尿液代谢物进行定量，以估计每种化合物的代谢程度。评估了四个肝毒性参数：肝脏重量、甘油三酯、葡萄糖-6-磷酸酶（G6P）活性和谷丙转氨酶（SGPT）活性。TRI显著影响肝脏重量和G6P活性；PER影响所有四个参数。TRI的代谢在1600毫克/千克以下与剂量呈线性关系，但随后变得饱和。PER的代谢是可饱和的。两种化合物受影响的肝毒性参数的剂量-效应曲线是非线性的，并且类似于相应溶剂的剂量-代谢图。在所有情况下，每种化合物的肝毒性数据与总尿液代谢物的关系图都是线性的，这表明PER和TRI对小鼠的肝毒性都与它们的代谢程度直接相关。这种模式与每种化合物主要代谢途径中有毒中间体的形成一致。
